青光眼的大脑蓝斑核结构及功能改变

Glaucoma is the first leading cause of irreversible blindness worldwide, the neurological damage of glaucoma is not only limited to the eye, but also affects central nervous system. A large number of studies have confirmed that the mechanism and characteristics of glaucoma were very similar to that of neurodegenerative diseases, such as Alzheimer's disease.In alzheimer's disease, locus ceruleus degeneration is ubiquitous.Locus ceruleus is the main part to synthesize norepinephrine in brain, literatures showed that electrical stimulation of locus ceruleus could reduce intraocular pressure of rabbit eyes,and norepinephrine was closely related to the metabolism of aqueous humor, etc. We made a preliminary research, found that resting-state brain function of locus ceruleus in glaucoma patients was significant difference with normal. Therefore, we hypothesize that, locus ceruleus dysfunction participates in the pathogenesis of glaucoma or disorder process of intraocular pressure, norepinephrine may play an important role. This project intends to carry out clinical and animal experiments, by glaucoma animal model and central administration, to study the relationship between intraocular pressure changes in glaucoma and changes of locus ceruleus and norepinephrine, in order to clarify morphological and functional changes of locus ceruleus in glaucoma, providing evidences for central pathogenesis and new target of clinical treatment in glaucoma.

青光眼是世界第一位不可逆致盲性眼病, 其神经损伤不仅局限于眼部，而且累及脑部中枢。大量研究证实青光眼与阿尔茨海默病等神经退行性疾病的发病机制和特点十分相似，阿尔茨海默病中，大脑蓝斑核的变性普遍存在，蓝斑核是脑内合成去甲肾上腺素的主要部位，文献显示电刺激蓝斑核可降低兔眼眼压、蓝斑核去甲肾上腺素能物质与眼内房水代谢密切关联等。我们进行初步探索，发现青光眼患者蓝斑核静息态脑功能较正常人存在显著差异。基于以上，我们假说：大脑蓝斑核功能紊乱参与青光眼的发病或眼压失调过程，去甲肾上腺素可能在其中扮演重要角色。本项目拟开展临床及动物实验，通过高场强磁共振观察不同分期青光眼患者蓝斑核的功能变化，通过青光眼动物模型及蓝斑核中枢给药研究青光眼眼压变化与蓝斑核形态学及去甲肾上腺素能物质改变的相互关系，阐明青光眼疾病过程中大脑蓝斑核及去甲肾上腺素能物质的改变及作用，为青光眼中枢发病机制及临床治疗新靶点提供依据。

目的：青光眼是世界首位不可逆性致盲性眼病，前期有学者研究青光眼损伤累及全脑，并且AD与青光眼有密切关系，甚至有研究者推测青光眼可能是眼部的AD，而蓝斑变性在AD的发病过程中起重要作用，本项目主要研究青光眼大脑蓝斑核结构及功能改变。.方法：临床研究部分，26例青光眼患者及26例年龄性别匹配的正常人，进行3T磁共振大脑静息态扫描，数据经后处理后，分析青光眼患者大脑蓝斑核低频振幅功能的变化及蓝斑核与全脑功能连接的改变。动物研究部分，分别使用青光眼大鼠模型及青光眼基因鼠，研究青光眼动物蓝斑核形态学及分子生物学功能改变。.结果：青光眼患者蓝斑核低频振幅脑功能活动增强，蓝斑核与大脑额叶、岛叶功能连接减低，与海马旁回功能连接增强。动物研究证实青光眼动物蓝斑核去甲肾上腺素能神经元数目减少，TH 及DβH 表达降低，TUNEL染色显示凋亡增加。.结论：青光眼存在大脑蓝斑核变性，可能通过去甲肾上腺素能神经元的功能异常参与发病。